HMO physician applauds Spitzer’s focus on information bias / NYT blind spot

HMO physician applauds Spitzer’s focus on information bias / NYT blind spot

Sun, 20 Jun 2004

The affirmation by a Kaiser Permanente physician, Dr. Kate Scannell, that NYS Attorney General, Eliot Spitzer, deserves applause for his “bold and courageous” lawsuit, is an encouraging watershed. The suit, she says, “gives me hope that we may be nearing high noon in New York, about to witness an overdue showdown between the commercial interests of the drug marketplace and the health interests of humanity that drug science should serve.”

Dr. Scannell reminds us: “The human stakes in this case are considerable, because researchers elsewhere have raised serious concerns that some antidepressants might actually increase the risk of suicide in children. Moreover, about 2.1 million paroxetine prescriptions were written for children in 2002.”

She urges the medical community and the FDA to come to Spitzer’s assistance because “he will need a good many deputies to help him.”

Recently uncovered evidence, however, shows that senior FDA officials have suppressed a report by Dr. Andrew Mosholder, FDA’s top expert whose recommendations to discourage the use of antidepressants in children, the Times reports: "would have been a monumental step. Antidepressants are among the biggest-selling drugs in the world and have long been viewed by doctors as relatively safe. Their use in children has been soaring."

FDA’s action to muzzle Dr. Moshlolder put greater value on protecting profits than children’s lives. In essence, FDA officials have been complicit in industry’s research concealment practices. When the concealed data revealed drug hazards, the FDA and the psychiatric establishment raised a straw man, seeking to redefine suicidal behavior. See Senator Chuck Grassley’s June 3, 2004, letter to FDA’s acting commissioner and Secretary of Health and Human Services, Tommy Thompson requesting all pertinent documents, including e-mail communication between FDA officials and drug company officials: http://finance.senate.gov/press/Gpress/2004/prg060304.pdf

In sharp contrast to the sobering reality checks by Senator Grassley and Attorney General Spitzer, a report in today’s New York Times fails to delve beneath the surface. The Times article fails to report institutional conflicts of interest–no matter how significant.

University-affiliated psychiatrists may pretend naiveté by claiming: “We’re just dealing with a lot of pieces of paper. We’re not dealing with people at all.” But an examination of their contractual agreements will reveal that they do not in fact, function in a pristine bubble. FDA’s choice of Columbia University as arbiters in the controversy over interpretation of evidence of suicidal behavior in children prescribed an antidepressant is being challenged.

Shouldn’t a NY Times business reporter find out how much money Columbia and its department of psychiatry garnered within the last 15 years from pharmaceutical companies (and industry-supported foundations) for psychiatric drug research?

Similar data should be obtained for other major psychiatric drug research centers, including: NYU, U Pittsburgh, UCLA, Johns Hopkins, U Maryland, U Texas.

AHRP questions:

  • the impartiality of Columbia employees inasmuch as the university receives substantial support from drug manufacturers;
  • the professional standards of those who claim that they can second guess from afar the difference between self-destruction and suicidal intent of children they have never met;
  • the motives of psychiatrists who are eager to sit in judgment of the professional judgment of those who had first hand knowledge of these children’s behavior;
  • the selection of psychiatrists who raised no objections to data concealment or tainted published reports.

Earlier this month, the Times reported, without documented evidence, that a new, unpublished Prozac trial in adolescents showed positive findings. But the Times did not see fit to report that a fully documented independent analysis comparing published and unpublished pediatric antidepressant trial data, published in The Lancet, found children at significant increased risk of suicidal behavior when prescribed an SSRI antidepressant compared to placebo.
See: http://www.thelancet.com/journal/journal.isa

Contact: Vera Hassner Sharav
Tel: 212-595-8974

TIMES STAR
It’s time to focus on information bias about drugs
By Dr. Kate Scannell
Sunday, June 20, 2004 –

HEARING about an exciting new drug study can make a pill sound so fantastic that we can hardly wait to take it. We rush to our doctor’s office to show her the newspaper clippings, and for extra measure we bring along a few supporting documents that we have downloaded from the Internet.

But suppose that one glorious study we heard about was just that — the one glorious study about that drug. Suppose that there existed three or four additional studies that made that drug seem undesirable or, at least, inglorious, and we had no way of knowing about them. Suppose those hidden studies contained information about side effects or contradictory data that suggested the drug really didn’t work.

It’s unsettling to consider these possibilities, but it’s important to remain vigilant about them. Clinically important — and generally unfavorable — information about drugs is often buried in publicly inaccessible archives. Our medical journals tend not to publish studies about drugs that were found to be duds in clinical trials.

Hidden drug data poses a serious and pervasive problem. For example, a recent study in the Journal of the American Medical Association analyzed 102 drug trials and found that 50 percent of efficacy data and 65 percent of harm outcomes were only partially reported.

In certain circumstances, the suppression of drug information can be heavy-handed. Researchers conducting trials funded by drug companies have been required to sign contracts that grant the companies the right to control which results get submitted for publication. A few years ago, a vaccine manufacturer even filed a multimillion-dollar lawsuit against a team of AIDS researchers who insisted on publishing results from a clinical trial that found the company’s HIV vaccine to be worthless.

Furthermore, because there is no one place where all data about drug trials and their results are stored, it becomes a bit of a scavenger hunt to find all knowable information about a drug that might interest you. This is not a healthy system when you don’t know where to look for drug information, and you can’t telepathically access what’s been kept out of publication.

A lawsuit filed this month in New York promises to challenge the formidable power of the pharmaceutical companies to pick and choose the information that gets disseminated and promoted in the public domain. New York Attorney General Eliot Spitzer has decided to sue drug manufacturer GlaxoSmith-Kline PLC, claiming that it committed consumer fraud by misrepresenting and withholding data about the use of its antidepressant paroxetine (Paxil) in children.

The human stakes in this case are considerable, because researchers elsewhere have raised serious concerns that some antidepressants might actually increase the risk of suicide in children. Moreover, about 2.1 million paroxetine prescriptions were written for children in 2002.

Mr. Spitzer alleges that the drug manufacturer skewed information about paroxetine by widely disseminating the single study that was able to showcase the drug in a positive light. He charges Glaxo with suppressing four other studies conducted on children and adolescents in the late 1990s that found paroxetine to be either ineffective or suspect for increasing the potential risk of suicide.

According to the Associated Press, the lawsuit also exposes an internal Glaxo document indicating that the company intended to “manage the dissemination of data in order to minimize any potential negative commercial impact.”

In summing up his mission, Mr. Spitzer succinctly stated his case: “Having doctors prescribe drugs without full knowledge of safety and efficacy is wrong.”

I applaud Mr. Spitzer’s efforts to drive out the forces that wittingly and unwittingly obscure or manipulate the information we need to evaluate the safety and efficacy of drugs. But he will need a good many deputies to help him.

Because the vast majority of drug trials are currently funded by the pharmaceutical companies, he will have to persuade that industry of the merits of his mission. If he’s lucky, federal regulators like the FDA will be armed with reporting requirements and riding at his side. Perhaps he can commandeer the public wagons to circle tight around the research industry, closing in with demands that it consistently reveal and disseminate all drug trial information — whether it is good, neutral, or bad.

Hopefully, the medical community will posse up en masse. So far, the American Medical Association and the publishers of a dozen major medical journals have called for proposals that require drug companies to register their studies in a central database at the outset of their trials. We could go further and decline arrangements with drug companies that allow them to own or silence the results of the research trials they fund.

Meanwhile, Mr. Spitzer’s move is bold and courageous. It gives me hope that we may be nearing high noon in New York, about to witness an overdue showdown between the commercial interests of the drug marketplace and the health interests of humanity that drug science should serve.

Kate Scannell is a physician with Kaiser Permanente and the author of “Death of the Good Doctor.”

~~~~~~~

THE NEW YORK TIMES
June 20, 2004
Antidepressants Restudied for Relation to Child Suicide
By GARDINER HARRIS

A child stabs himself in the neck with a pencil. Another slaps herself in the face. Is either suicidal? It is a question that has divided psychiatrists and drug regulators the world over and goes to the heart of a fierce controversy over whether antidepressants lead some children to become suicidal.

Now four researchers at Columbia University hope to provide an answer. By reclassifying reports of suspect or self-destructive behavior that occurred during tests of antidepressants in youngsters, the research team hopes to clarify whether antidepressants lead children and teenagers to become suicidal. Officials at the Food and Drug Administration say they will use results of the study to help them decide, later this summer, whether the agency should discourage doctors from prescribing the pills to youngsters.

The study was commissioned by top F.D.A. officials after they rejected an analysis by one of the agency’s top experts that concluded that antidepressants could be dangerous when given to teenagers and younger children. With such a controversial beginning, the study is being met by fierce criticism.

Senator Charles E. Grassley, Republican of Iowa, issued a statement questioning whether the study was part of an effort by the Food and Drug Administration to suppress the truth about the risks of antidepressants. Mr. Grassley said he was investigating the study as part of a larger inquiry into the agency’s handling of the controversy involving antidepressants and suicide.

Some prominent mental-health research has questioned the study’s methodology.

“You’ve asked the Columbia group to take data that’s suboptimal and try to come up with a conclusion, and I really doubt that they will be able to do that,” said Dr. Thomas R. Insel, director of the National Institute for Mental Health.

The Columbia team plans to apply a consistent definition of ”suicidal” to a disparate collection of more than 400 reports of adverse behavior that occurred in 25 clinical tests of nine antidepressants. The tests, undertaken by drug companies, involved Prozac, Zoloft, Paxil, Luvox, Celexa, Wellbutrin, Remeron, Serzone and Effexor.

One of the problems with the drug-company trials is that they tend to confuse self-destructiveness with suicidal attempts, team members said in an interview.

“Suicide research has come up with a specific definition of suicide attempts: a self-injurious behavior where there is some intent to die,” said Barbara Stanley, one of the researchers.

The team will give nine independent reviewers the descriptions that drug-company researchers used in reporting the cases involving adverse behavior. . The reviewers will label each event as suicidal, nonsuicidal or indeterminate, and then give the data to federal drug regulators for statistical analysis.

Discovering intent from the brief notes provided by the drug companies could be difficult. In a speech before an advisory panel in February, Dr. Thomas Laughren, leader of the F.D.A.’s psychiatric drug products group, noted that the drug companies’ descriptions were often poor. “We did not have the level of detail in these cases that one would have liked to do a rational classification,” Dr. Laughren said.

Julie Magno Zito, an associate professor of pharmacy and psychiatry at University of Maryland, Baltimore, predicted the Columbia team would not be able to overcome this problem. “If a kid pierces his neck with a pencil, that could be a violent act of self-destruction or it could have been nothing,” Dr. Zito said. “If the notes don’t make the intent clear, how do you interpret that?”

Dr. Zito called the Columbia study “a fundamentally bad idea.”

Dr. Alan Gelenberg, head of the department of psychiatry at the University of Arizona, said the study would provide a needed perspective. But even those who support the study agree that it is unlikely to change many minds on the question of whether antidepressants should be prescribed to children. “This question will never be settled,” said Dr. James McGough, a professor of clinical psychiatry at the University of California, Los Angeles. “Still, I’m eager to see what their answer is.” In tackling the issue, the researchers say they understand that they are being thrust into a maelstrom rarely seen in psychiatry. “For all of us, our anxiety levels are higher because we know that there are people invested in this one way or the other,” said Dr. Madelyn Gould, professor of clinical public health in psychiatry. “Anything that has to do with drug treatment in kids is so emotionally charged.”

The study had its beginnings early last year when GlaxoSmithKline submitted to federal drug regulators the results of three trials of its Paxil antidepressant in teenagers and other children. The company had undertaken the studies to take advantage of a federal law that delays by six months the introduction of cheaper, generic versions of drugs when branded makers test medicines in children.

In GlaxoSmithKline’s trials, depressed young people given Paxil fared no better than those given placebos. It was a disappointing result for GlaxoSmithKline but had no effect on its application for the six-month extension. Still, a reviewer at the Food and Drug Administration noticed something strange about the trials: teenagers given Paxil suffered more problems of ”emotional lability,” or instability, than those given a placebo.

The reviewer, Dr. Andrew Mosholder, thought ”emotional lability” was overly broad. He asked the company to resubmit its data, this time using a separate category for suicide. That report, given in May to both American and British health authorities, was alarming. Teenagers and younger children given Paxil were much more likely to become suicidal than those given placebos. In June, both the British and American authorities warned doctors against prescribing Paxil to youngsters. Worried that the problem could extend far beyond Paxil, the F.D.A. in July asked the makers of eight other antidepressants to submit data from their studies in youngsters.

In August, Wyeth issued a warning that doctors should avoid prescribing Effexor to youngsters because it, too, seemed to cause them to become more suicidal.

By September, the agency had received the other companies’ studies. Looking at them all, Dr. Mosholder concluded that children given antidepressants were almost twice as likely as those given placebos to become suicidal. He suggested the agency discourage the drugs’ use in children. It would have been a monumental step. Antidepressants are among the biggest-selling drugs in the world and have long been viewed by doctors as relatively safe. Their use in children has been soaring.

Dr. Mosholder’s bosses at the Food and Drug Administration, however, said the drug company data was inconsistent and that some events termed ”possibly suicidal” seemed innocent. Top agency officials hired the Columbia researchers to review the data, and they forbade Dr. Mosholder to speak about his conclusions to an advisory panel reviewing the matter. The silencing of Dr. Mosholder prompted outrage among critics of antidepressants and the ongoing investigation by Senator Grassley. It also has fostered skepticism about the Columbia study. Already, Internet postings are questioning the backgrounds of the Columbia researchers. One asks whether Kelly Posner, the lead investigator, has participated in trials financed by the drug industry.

In a group interview in a conference room in the New York State Psychiatric Institute, the researchers said they were unbiased. Dr. Posner said that she had participated in some trials sponsored by drug makers but never as a principal investigator. All of the trials involved attention deficit disorder, not depression or suicide, she said. Her three colleagues said that they had never taken part in a drug-company trial. And they said that their study, while hugely controversial, was relatively simple: figuring out the appropriate labels to place on the behaviors in the individual cases. “We’re just dealing with a lot of pieces of paper,” Dr. Gould said. “We’re not dealing with people at all. And all the interesting questions happen once we give the data over to the F.D.A.,” where the statistical analysis will occur.

Copyright 2004 The New York Times Company